Periodontal disease is the major cause of tooth loss in the elderly, and is characterized by bacterial inflammation leading to loss of tooth-supporting structures. It is estimated that nearly 60 percent of adult Americans suffer from some form of the disease. Currently, there are no cures, and treatment is aimed at preventing further disease progression. The molecular events that ensue when oral bacteria interact with the first immunological barrier, epithelium, are largely unknown. Recently, several homologous effector systems have been identified in the pathogen recognition systems of plants, flies and mammals. Some of the proteins with homologous structures include the IL-1 receptor, Drosophila and human Toll proteins. These receptors have common signaling systems and may represent an ancient and highly conserved mechanism for fighting pathogens. The role of these proteins in the host response to periodontal pathogens has not been widely elucidated. We propose the hypothesis that periodontal pathogens interact human Toll receptors on keratinocytes, resulting in activation of NF-kappaB. This signaling pathway results in upregulation of NF-kappaB- responsive cytokines such as IL-1 and TNF, resulting in periodontal inflammation and osteoclast activation.